Findings

This mutation was first identified in a woman from Australia who developed forgetfulness and depression in her late 20s (Taddei et al., 1998). By age 34 she also had an abnormal gait and brisk (increased) reflexes. Genetic analysis of exons 16 and 17 of APP showed no additional mutations. Her family history is largely unknown, but her father reportedly died from a progressive neurological disease in his 40s. Segregation with disease could not be determined.

This mutation was later identified in a woman from the United Kingdom who developed a progressive parkinsonian syndrome at age 42 (Beck et al., 2004). Her symptoms also included mild spastic paraparesis and dementia. She died at age 58, after a 16-year disease course. AD was diagnosed at autopsy. Postmortem examination revealed frequent Aβ plaques, many of the cotton-wool type, and severe neurofibrillary tangle pathology (Braak and Braak stage VI). Genetic screening of her peripheral lymphocytes failed to reveal mutations, but the P436Q mutation was detected in DNA isolated from her cerebral cortex, indicating mosaicism. The woman’s parents were both unaffected at the time of their deaths, one at age 73 and the other at 37, and none of her six siblings were affected by neurodegenerative disease at the time of the report. Therefore, the P436Q mutation is thought to have occurred de novo in this woman. Given that the mutation was detected in her brain, but not in lymphocytes, it is thought to have arisen during gastrulation, perhaps in the inner cell mass of the blastocyst.

The daughter of the mutation carrier described above developed a different neurodegenerative phenotype at the age of 27. She developed a progressive cerebellar syndrome with spastic paraparesis and dementia. She died 12 years after diagnosis. No autopsy was performed. The mutation was detectable in her peripheral lymphocytes and appears to have been inherited as a germline mutation.

Neuropathology

Neuropathology consistent with AD in at least one mutation carrier, including frequent Aβ plaques, many of the cotton-wool type, and severe neurofibrillary tangle pathology (Braak and Braak stage VI) (Beck et al., 2004).